5-(2-Aminophenyl)pyrazole-3-carboxylic acids and esters thereof

ABSTRACT

5-(2-Aminophenyl)pyrazole-3-carboxylic acids, useful as intermediates in the preparation of compounds useful as complement inhibitors, are prepared by reacting a 2nitroacetophenone with a dialkyl oxalate in the presence of a strong base and in an inert solvent to give the corresponding alkyl 2-nitrobenzoylpyruvate, condensing the alkyl 2nitrobenzoylpyruvate with hydrazine in an inert solvent to give an alkyl 5-(2-nitrophenyl)-pyrazole-3-carboxylate, reducing the nitro group catalytically to give the alkyl 5-(2aminophenyl)pyrazole-3-carboxylate, and, if desired, hydrolyzing the ester to the free acid.

[4 1 Aug. 12, 1975 5-( 2-AMINOPHENYL)PYRAZOLE-3- CARBOXYLIC ACIDS ANDESTERS THEREOF ['75] Inventor: James H. Wikel, Greenwood, Ind.

[73] Assignee: Eli Lilly and Company, Indianapolis,

Ind.

22 Filed: Apr. 12,1974

21 App1.No.: 460,646

[52] US. Cl. 260/310 R; 424/273 [51] Int. Cl C07d 47/02 [58] Field ofSearch 260/310 R Chemical Abstracts Vol. 52: 3784g (1956). ChemicalAbstracts Vol. 66: 75947k (1967).

Primary ExaminerDonald B. Moyer Attorney, Agent, or Firm-William E.Maycock; Everet F. Smith [57] ABSTRACT5-(2-Aminophenyl)pyrazole-3-carboxylic acids, useful as intermediates inthe preparation of compounds useful as complement inhibitors, areprepared by reacting a Z-nitroacetophenone with a dialkyl oxalate in thepresence of a strong base and in an inert solvent to give thecorresponding alkyl Z-nitrobenzoylpyruvate, condensing the alkyl2-nitrobenzoylpyruvate with hydrazine in an inert solvent to give analkyl 5-(2- nitrophenyl)-pyrazole-3-carboxy1ate, reducing the nitrogroup catalytically to give the alkyl 5-(2-aminophenyl)pyrazo1e-3-carboxylate, and, if desired, hydrolyzing theester to the free acid.

2 Claims, No Drawings -(Z-AMINOPHENYL)PYRAZOLE-S-CARBOXYLIC ACIDS ANDESTERS THEREOF BACKGROUND OF THE INVENTION This invention relates to5-(2-aminophenyl)pyrazole- 3-carboxylic acids and alkyl esters thereof.More particularly, this invention relates to 5-(2-aminophenyl)pyrazole-3-carboxylic acids and alkyl esters thereof whichare useful as intermediates in the preparation of compounds useful ascomplement inhibitors, and to a process for preparing said 5-(2-aminophenyl)pyrazole-3-carboxylic acids and esters.

Malfunction of the serum complement system is known to be involved inglomerulonephritis and is believed to be involved in serum sickness andin certain inflammatory diseases such as rheumatoid arthritis.Consequently, an effective complement inhibitor would substantiallyblock the malfunction of the serum complement system and hence would beuseful in the treatment of such diseases.

SUMMARY OF THE INVENTION In accordance with the present invention, novel5-(2- aminophenyl)pyrazole-3-carboxylic acids and alkyl esters thereofare provided having the following general formula:

COOR R3 I wherein R is hydrogen or C -C alkyl and R and R3 aremonovalent groups independently selected from the group consisting ofhydrogen, methyl, methoxy, fluoro, chloro, and bromo, with thelimitation that R and R must be different unless each of R and R ishydrogen.

The compounds of the present invention are prepared by the process whichcomprises the steps of l) reacting a Z-nitroacetophenone with a C Cdialkyl oxalate in the presence of a strong base, in an inert solvent,and at a temperature of from about 40C to about 100C, and thenacidifying the reaction mixture to give the corresponding alkyl 2-nitrobenzoylpyruvate; (2) condensing the alkyl 2- nitrobenzoylpyruvatewith hydrazine in an inert solvent and at a temperature of from about 0Cto about 100C to give an alkyl 5-(2-nitrophenyl)pyrazole-3- carboxylate;(3) reducing catalytically the nitro group of the alkyl5-(2-nitrophenyl)pyrazole-3carboxylate, in an inert solvent, at aninitial hydrogen pressure of from about 15 to about 100 psig, and at atemperature of from about 0C to about C, to give the alkyl 5-(2-aminophenyl)pyrazole-3-carboxylate; and, if desired, (4) hydrolyzing thealkyl 5-( 2-aminophenyl)-pyrazole- 3-carboxylate to the free acid.

The compounds of the present invention are useful as intermediates inthe preparation of certain 5-[2-(N- substitutedamino)phenyl]pyrazole-3-carboxylic acids which are useful as complementinhibitors.

DETAILED DESCRIPTION OF THE INVENTION Examples of compounds comingwithin the foregoing general formula include, among others,

5-( 2-Aminophenyl )pyrazole-B-carboxylic acid, Methyl5-(2-aminophenyl)pyrazole-3-carboxylate, Ethyl 5-(Z-aminophenyl)pyrazole-3-carboxylate, Propyl5-(Z-aminophenyl)pyrazole-3-carboxylate, Isopropyl5-(2-aminophenyl)pyrazole-3-carboxylate, Methyl5-(2-amino-3-methylphenyl)pyrazole-3- carboxylate, Isopropyl5-(2-amino-4-fluorophenyl)pyrazole-3- carboxylate, Methyl5-(2-amino-6-methoxyphenyl)pyrazole-3- carboxylate, 52-Amino-3-methyl-6-methoxyphenyl )pyrazole-3- carboxylic acid, Ethyl5-(2-amino-3-methyl-5- bromophenyl)pyrazole-S-carboxylate, and Methyl5-(2-amino-4-chIoro-5- methoxyphenyl)pyrazole-3-carboxylate. Thereferred compounds are the esters; i.e., R preferably is C -C alkyl.

The process of the present invention can be represented by the followingreaction scheme:

0 II II 11 0-0 -C-OR H base solvent solvent C003 00R R catalyst Nosolvent 2 wherein R is C -C alkyl and R and R are as definedhereinbefore. Briefly, a 2-nitroacetophenone is reacted with a dialkyloxalate in the presence of a strong base and in an inert solvent, thenthe reaction mixture is acidified to give the corresponding alkyl 2-nitrobenzoylpyruvate. The alkyl 2- nitrobenzoylpyruvate then iscondensed with hydrazine in an inert solvent to give an alkyl 5-(2-nitrophenyl)pyrazole-S-carboxylate. The nitro group of the alkyl5-(Z-nitrophenyl)pyrazole-3-carboxylate is reduced catalytically in aninert solvent to give the alkyl 5-(2-aminophenyl)pyrazole-3-carboxylate.Optionally, but not preferably, the alkyl 5-(2-aminophenyl)pyrazole-3-carboxylate can be hydrolyzed by known methods tothe 5-(2- aminophenyl)pyrazole-3-carboxylic acid.

The first step, which involves reacting a 2- nitroacetophenone with adialkyl oxalate, preferably with dimethyl oxalate, essentially is aknown procedure. See, for example, L. Musajo, et al., Gazz. chim. ital.,80, 161 (1950) [C.A., 45, 624 (1951)], and K. Makino, et al., KumamotoMed. 1., 6, 122 (1954) [C.A., 49, 6179 (1954)]. In general, bothstarting materials are either commercially-available or readily preparedby known procedures. Normally and preferably, the molar ratio of theZ-nitroacetophenone to the dialkyl oxalate will be about 1:1, althoughan excess of either reactant can be employed, if desired. Thus, saidmolar ratio can vary from about 2:1 to about 1:2. The molar ratio ofstrong base to the dialkyl oxalate can vary from about 1:1 to about1.2:1, and preferably from about 1:1 to about 1.1:1. Most preferably,the molar ratio of base to oxalate will be about 1:1. Examples ofsuitable strong bases include, among others, alkali metal hydroxides,such as lithium hydroxide, sodium hydroxide, potassium hydroxide,rubidium hydroxide, and cesium hydroxide; alkali metal C C, alkoxides,such as sodium methoxide, potassium ethoxide, lithium isopropoxide,cesium propoxide, rubidium butoxide, sodium sec-butoxide, lithiumt-butoxide, and the like; C -C alkyl lithium compounds, such as methyllithium, ethyl lithium, propyl lithium, isopropyl lithium, butyllithium, sec-butyl lithium, isobutyl lithium, and t-butyl lithium;alkali metal hydrides, such as lithium hydride, sodium hydride,potassium hydride, rubidium hydride, and cesium hydride; and the like.The preferred bases are the alkali metal alkoxides. Of course, the basemust be significantly soluble in the reaction solvent, and preferablywill be substantially, i.e., at least about 50 percent, soluble. Mostpreferably, the base will be completely soluble in the reaction solvent.Generally, the solvent must be inert. Examples of such solvents include,among others, alkanols, such as methanol, ethanol, propanol, andisopropanol; aromatic hydrocarbons, such as benzene, toluene, thexylenes, and the like; aliphatic hydrocarbons, such as pentane, hexane,octane, and the like; ethers, such as diether ether, diisopropyl ether,methyl butyl ether, tetrahydrofuran, 1,4-dioxane, and the like; and suchmiscellaneous solvents as N,N-dimethylformamide, N,N- dimethylacetamide,and dimethyl sulfoxide. The preferred solvents are the alkanols. Thechoice of a particular preferred solvent is important only when it isdesired to isolate the alkyl 2-nitrobenzoylpyruvate in pure form. Thatis, when the alkyl moiety of the alkanol solvent is different from thealkyl moiety of the dialkyl oxalate, transesterification can result inthe formation of two alkyl 2-nitrobenzoylpyruvates having differentalkyl moieties. Consequently, when using an alkanol solvent, it ispreferred that the alkyl moieties of the alkanol and the dialkyl oxalatebe the same. The amount of solvent employed is not critical, providedadequate agitation can be maintained during the reaction. Typically, theamount of solvent employed will constitute about 50 percent by weight ofthe total reaction mixture. The reaction temperature, which can varyfrom about 40C to about 100C, is to some extent dependent upon thebase-solvent combination employed. When both a preferred base and apreferred solvent are used, the reaction temperature can vary from about20C to about 20C. The reaction time is not critical and can vary fromabout 15 minutes to about 24 hours. Typically, the reaction time willvary from about 1 to about 18 hours. When the reaction is complete, thealkyl 2-nitrobenzoyl-pyruvate normally has precipitated as the enolate.The precipitate is isolated and dissolved in water. Acidification of theresulting aqueous solution results in the precipitation of the alkyl 2-nitrobenzoylpyruvate which can be purified, if desired, by standardtechniques. The acid used in said acidificatioon is not critical and canbe either organic or inorganic. Examples of suitable acids include,among others, organic carboxylic acids, such as acetic acid, propionicacid, chloroacetic acid, trichloroacetic acid, benzoic acid,m-nitrobenzoic acid, pbromobenzoic acid, and the like; organic sulfonicacids, such as methanesulfonic acid, ethanesulfonic acid,benzenesulfonic 'acid, p-toluenesulfonic acid, and the like; andinorganic acids, such as hydrochloric acid, sulfuric acid, phosphoricacid, and the like. The organic acids are preferred, with the organiccarboxylic acids being most preferred.

The second step of the process of the present invention requirescondensing hydrazine with the alkyl 2-nitrobenzoyl-pyruvate obtainedabove. In general, the molar ratio of hydrazine to the alkyl 2-nitrobenzoylpyruvate can vary from about 1:1 to about 3 :1 or evenhigher. Preferably, this molar ratio will vary from about 1:1 to about1.1:1. In general, any inert solvent can be used. Examples of suchsolvents include those listed as suitable in the first step, andadditionally, aliphatic carboxylic acid esters, such as methyl acetate,ethyl acetate, butyl acetate, and the like; and halogencontaininghydrocarbons, such as methylene chloride, ethylene dichloride,chloroform, carbon tetrachloride, chlorobenzene, bromobenzene, and thelike. The preferred solvents are the alkanols. The amount of solventemployed is not critical, although the solvent normally will constituteat least about 50 percent by weight of the total reaction mixture.However, the solvent often will constitute up to about percent by weightof the total reaction mixture when the alkyl 2- nitrobenzoylpyruvate hasbut limited solubility in the solvent. The reaction temperature can varyfrom about 0C to about C, preferably from about 10C to about 40C, andmost preferably will be ambient temperature. The parameters discussedhereinabove with respect to the reaction time in the first step applyhere, also. The alkyl 5 2-nitrophenyl )pyrazole-3 carboxylate which isobtained is isolated and, if desired, purified in accordance withstandard procedures. It should be noted that the alkyl 5-(2-nitrophenyl)pyrazole-3-carboxylate is light-sensitive; i.e., thecompound turns to a lavender to purple color upon exposure to light.Consequently, it is desirable to the appropriate precautions whilecarrying out the second step, which precautions are well known to thoseskilled in the art. However, the color change which occurs upon exposureof the compound to light apparently has no significant effect upon thechemical structure of the compound.

In the third step of the process of the present inven- NHg tion, thenitro group of the alkyl 5-(2- nitrophenyl)pyrazole-B-carboxylate iscatalytically reduced to an amino group in accordance with knownprocedures. Briefly, the compound is dissolved in an inert solvent,examples of such solvents being those listed with respect to step twoabove. Again, the preferred solvents are the alkanols. The amount ofsolvent is not critical and typically will constitute from about 50 toabout 95 percent by weight of the total reaction mixture. Suitablecatalysts include, among others, 5 percent rhodium on alumina, 5 percentrhodium on activated charcoal, ruthenium oxide, platinum oxide, 5percent palladium on activated charcoal, and other like catalysts knownto catalyze the reduction of aromatic nitro groups. The amount ofcatalyst employed can vary from about 0.1 percent to about percent byweight, based on the amount of alkyl 5-( 2-nitrophenyl)pyrazole-S-carboxylate; about ten percent by weight ofcatalyst has been found to give satisfactory results. The initialhydrogen pressure can vary from about 15 'to about 100 psig, with fromabout to about 60 psig being preferred. The reduction temperaturenormally will vary from about 0C to about C. The reduction isexothermic; hence, some care must be exercised to keep the reductionunder control. The reaction mixture is worked up according to standardprocedures in order to isolate the alkyl 5-( 2-aminophenyl)pyrazole'3-carboxylate which can be purified, if desired.

As indicated hereinbefore, an optional fourth step can be carried out,if desired, which step comprises hydrolyzing by known procedures thealkyl 5-(2- aminophenyl)pyrazole-B-carboxylate to the corresponding5-(2-aminophenyl)pyrazole-3-carboxylic acid. This fourth step, however,is not preferred since the carboxylic acid moiety of the compounds ofthe present invention must be blocked in order to convert the compoundsof the present invention to certain 5-[2 (N-substituted amino )phenylpyrazole-3-carboxylic acids which are useful as complement inhibitors.

The compounds of the present invention are converted to the complementinhibiting pyrazole-3- carboxylic acids in accordance with the followingreaction scheme:

COOR

DMF

IH OH 9 A EtOH/H O R2 1 wherein R R and R are as defined hereinbefore; Ris a monovalent group selected from the group consisting of methyl,benzyl, and monosubstituted benzyl in which the substituent is methyl,trifluoromethyl, methoxy, methylsulfonyl, fluoro, chloro, or bromo; andX is fluoro, chloro, or bromo. Thus, an alkyl 5-( 2-aminophenyl)pyrazole-3-carboxylate is treated with phosgene in a largeexcess of pyridine to give the corresponding alkyl pyrazolo[l,5-c]quinazolin-5(6H)-one- 2-carboxylate. The pyrazoloquinazolinonethen is N- alkylated at the 6-position with an alkyl or aralkyl halidein the presence of a strong base, such as sodium hydride, and in thepresence of a suitable solvent, such as N,N-dimethylformamide. Theresulting 6-substituted pyrazoloquinazolinone is hydrolyzed to thecorresponding 5-[2-(N-substituted amino)phenyl]pyrazole- S-carboxylicacid, typically by heating at reflux a mixture of the 6-substitutedpyrazoloquinazolinone, potassium hydroxide, and aqueous ethanol. Thereaction mixture then is cooled and made acidic with aqueoushydrochloric acid. The solid which forms is isolated by filtration andpurified, if desired, according to known methods.

It will be apparent that in converting a compound of the presentinvention to a complement-inhibiting pyrazole-3-carboxylic acid, anycarboxylic acid blocking group can be employed which is stable duringthe conversion and yet capable of being readily removed.

The pyrazole-3-carboxylic acids obtained from compounds of the presentinvention are useful in inhibiting complement-induced hemolysis.Complement inhibitors find practical utility in the treatment of suchdiseases as glomerulo-nephritis, serum sickness, and certaininflammatory diseases such as rheumatoid arthritis.

Utilization of a complement inhibitor in general involves administeringto a mammal parenterally, preferably intravenously or intraperitoneally,an effective amount of such a compound, typically at a dosage levelsufficient to provide a concentration of the compound in the blood offrom about 1 to about 400 ug/ml. Such a concentration on the average canbe attained by the administration of a dose of from about 0.05 to about32 mg/kg. The necessary concentration in the blood of complementinhibitor can be achieved by administering a single dose or up to aboutsix smaller doses per day, depending upon the tolerance of the patientto the compound, persistence of the compound in the blood stream, andother factors. The complement inhibitor normally is formulated into asuitable pharmaceutical composition comprising the active ingredient inassociation with at least one pharmaceutically-acceptable carriertherefor by procedures well known in the art.

Suitable pharmaceutical carriers are described in E. W. Martin, et al.,Remingtons Pharmaceutical Sciences, 14th Ed., Mack Publishing Company,Easton, Pa., 1965.

In addition to parenteral administration, the complement inhibitor canbe administered to a mammal enterally, preferably orally. For enteraladministration, the complement inhibitor normally is administered at alevel of from about 1 to about 200 mg/kg of mammal body weight.Advantageously, the complement inhibitor is formulated in a dosage unitform containing from about 5 to about 500 mg, preferably from about toabout 150 mg, of active ingredient in association with suitablecarriers, diluents, and the like.

The present invention is more fully described, without intending tolimit it in any manner, by the following examples which illustrate thepreparation of a compound of the present invention by means of theprocess of the present invention. In the examples, all temperatures arein degrees centigrade, unless otherwise specified.

EXAMPLE 1 Preparation of methyl 2-nitrobenzoylpyruvate To a solution of20 g of sodium methoxide and 43 g of dimethyl oxalate in 150 ml ofmethanol, under nitrogen and at a temperature of 0, was added dropwise60 g of 2-nitroacetophenone. The reaction mixture was allowed to warmslowly to ambient temperature and was stirred at ambient temperatureovernight. To the solidified reaction mixture was added 125 m] ofdiethyl ether. The resulting slurry was filtered and the solid waswashed thoroughly with additional diethyl ether. The dried solid wasdissolved in about 1200 ml of water. The resulting solution was filteredto remove insoluble material. The filtrate was acidified with glacialacetic acid and cooled, and the precipitated solid was isolated byfiltration to give, after drying, 77 g (84 percent) of methylZ-nitrobenzoylpyruvate, mp 9495. The following elemental analysis wasobtained. Calculated for C11H9NO6:

C, 52.60; H, 3.61; N, 5.58; O, 38.22 Found:

C, 52,38; H, 3.56; N, 5.44; O, 38.44

EXAMPLE 2 Found:

C, 53.42; H, 3.37; N, 17.26; 0, 25.96

EXAMPLE 3 Preparation of methyl 5-(2-aminophenyl)pyrazole-3-carboxylate.

Methyl 5-( 2-nitrophenyl)pyrazole-3-carboxylate was reduced, using 25 gof the nitro compound, 570 ml of ethanol, 2.5 g of 5 percent palladiumon activated characoal, and an initial hydrogen pressure of 55 psig. Thereduction required 1.5 hours, during which time the reaction temperatureincreased from ambient temperature to about 54. Hydrogen uptake was 92percent of theory. The reaction solution was treated with decolorizingcarbon and filtered. The filtrate was distilled under reduced pressureto give 15 g (69 percent) of crude product which upon recrystallizationfrom benzene/hexane gave 7.4 g of methyl 5-(2-aminophenyl)pyrazole-3-carboxylate, mp 1 3 1-l 32. The followingelemental analysis was obtained. Calculated for C H N O C, 60.82; H,5.10; N, 19.34; 0, 14.73 Found:

C, 60.87; H, 5.01; N, 19.52; 0, 14.98

What is claimed is:

1. A compound of the formula,

wherein R is hydrogen or C -C alkyl and R and R are monovalent groupsindependently selected from the group consisting of hydrogen, methyl,methoxy, fluoro, chloro, and bromo, with the limitation that R and Rmust be different unless each of R and R is hydrogen.

2. The compound of claim 1, wherein R is C -C alkyl.

1. A COMPOUND OF THE FORMULA,
 2. The compound of claim 1, wherein R1 isC1-C3 alkyl.